Tissue-resident Macrophage Enhancer Landscapes Are Shaped by the Local Microenvironment


Yonit Lavin, Deborah Winter, Ronnie Blecher-Gonen, Eyal David 2, Hadas Keren-Shaul, Miriam Merad, Steffen Jung, Ido Amit


Macrophages are critical for innate immune defense and also control organ homeostasis in a tissue-specific manner. They provide a fitting model to study the impact of ontogeny and microenvironment on chromatin state and whether chromatin modifications contribute to macrophage identity. Here, we profile the dynamics of four histone modifications across seven tissue-resident macrophage populations. We identify 12,743 macrophage-specific enhancers and establish that tissue-resident macrophages have distinct enhancer landscapes beyond what can be explained by developmental origin. Combining our enhancer catalog with gene expression profiles and open chromatin regions, we show that a combination of tissue- and lineage-specific transcription factors form the regulatory networks controlling chromatin specification in tissue-resident macrophages. The environment is capable of shaping the chromatin landscape of transplanted bone marrow precursors, and even differentiated macrophages can be reprogrammed when transferred into a new microenvironment. These results provide a comprehensive view of macrophage regulatory landscape and highlight the importance of the microenvironment, along with pioneer factors in orchestrating identity and plasticity.

Dataset information:

Genomic assay Bulk RNA-seq Samples Microglia, Kupffer cells, spleen, lung, peritoneal, ileal, colonic MFs and monocytes
Method for deriving gene sets K-means Number of gene sets 11
Figure source Figure 1 Data source Table S1

Associated gene sets:

Gene set # Description No. of genes
1 Microglia 577
2 Kupffer cells & Spleen MΦ 287
3 Kupffer cells & Spleen & Lung MΦ 446
4 Lung MΦ 234
5 Lung & Peritoneal MΦ 177
6 Peritoneal MΦ 259
7 Ileal & Colonic MΦ 276
8 Monocytes 226
9 Shared 193
10 Shared 201
11 Shared 128

A total of 3004 genes are associated with this dataset.